HIV infection induces severe depletion of peripheral T lymphocytes. The thymus is the source of new T cells, however this tissue undergoes age-associated involution, such that naive T cell production declines with age. It is therefore difficult to reconstitute naive T cell immunity in adults who lose peripheral T cells. This proposal centers around ascertaining factors responsible for age-associated thymic involution, with the hope of using this knowledge to eventually increase thymic function and thereby increase reconstitution of the immune system, in individuals suffering T cell loss due to severe HIV disease or those undergoing hemato-ablative therapy for malignancies. Our preliminary studies have found that the mRNA expression of several proteins associated with the insulin-like growth factors (termed here "IGF Axis proteins") is altered in the adult versus fetal thymus. Members of this group have previously been shown to be involved in normal thymopoiesis and with involution of other organs. Strikingly, we have noted that the expression of insulin-like growth factor binding protein-5 (IGFBP-5) RNA is elevated on average 100-fold in adult versus fetal thymi. This increase in expression occurs well after birth, consistent with the onset of thymic involution. Additional members of this family, including IGF-II, IGFBP-2 and IGFBP-4 are differentially expressed between human fetal and adult thymi. We propose two Specific Aims designed to determine the role of these proteins in thymic involution: 1) To evaluate the role of IGFBP-5 in age-associated human thymic involution and reduced T cell production; 2) Determine the role of other members of the "IGF Axis" in human thymic involution. We have at our disposal both in vivo (the SCID-hu mouse) and in vitro (adult and fetal thymic organ culture) models to decipher what roles these proteins play in thymic involution. We hope that these studies will identify novel targets for new therapeutic approaches designed to augment immune reconstitution in HIV disease and cancer. [unreadable] [unreadable]